This invention relates to novel compounds and, more particularly, to novel derivatives of fatty acid analogs that have from one to three heteroatoms in the fatty acid moiety which can be oxygen, sulfur or nitrogen, and in which the carboxy-terminus has been modified to form, e.g., various amides, esters, ketones, alcohols, alcohol esters and nitriles thereof.
These novel compounds are useful as anti-viral and anti-fungal agents or pro-drugs of such agents and are particularly useful as inhibitors of retroviruses, especially lentiviruses such as the human immunodeficiency virus (HIV).
The fatty acid acylation of specific eukaryotic proteins is a well-established process. See, e.g., the review article by Towler et al., Ann. Rev. Biochem. 57, 69-99 (1988), and references cited therein.
Fatty acid analogs containing heteroatom replacements of methylene groups in the fatty acid chain by oxygen, sulfur and nitrogen have been shown to have various anti-viral and antifungal activity. See, e.g.,
Bryant et al., Proc. Natl. Acad. Sci. USA 86, 8655-8659 (1989);
Bryant and Ratner, Proc. Natl. Acad. Sci. USA 87, 523-527 (1991);
Doering et al., Science 252, 1851-1854 (1991);
Bryant et al., Proc. Natl. Acad. Sci. USA 88, 2055-2059(1991);
and Devadas et al., J. Biol. Chem. 267, 7224-7239 (1992).
See also,
U. S. Pat. Nos. 5,073,571; 5,082,967; 5,151,445;
and EPO published patent applications EP 327,523 and EP 480,901.
In French Patent application 2,657,259, N-myristoyl-(S)-phenylalanine is disclosed as an inhibitor of NMT for treatment of cancer and retroviral infection, e.g. AIDS. Antiviral myristoylglycine is disclosed in Japanese Patent applications 62-126384 and 62-255810. These reported myristoylamino acids do not contain heteroatoms in the myristic acid moiety.